Compositions containing LYCD and other topically active medicinal ingredients

ABSTRACT

A composition comprising LYCD together with known topically active useful medicinal agents such as antiwrinkling, antibiotic, anticancer, antifungal, antiinflammatory, antiviral, steroid, and wound healing agents. The LYCD works together with the other active ingredients to achieve a synergistic result more effective than can be obtained from the topical agents individually, and more effective than could be predicted from the mere addition of the known efficacies of the individual ingredients.

RELATED APPLICATION

The present application is a continuation-in-part of pending applicationU.S. Ser. No. 07/159,390, filed Feb. 23, 1988, of the present inventor,Robert H. Levin.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to medicinal compositions, and moreparticularly refers to such compositions having active medicinalingredients, and additionally having LYCD in amounts sufficient to actwith the other active ingredients to provide synergistic therapeuticresults.

2. Description of the Prior Art

LYCD as utilized herein in the specification and claims is the acronymfor Live Yeast Cell Derivative. The material is also known as SkinRespiratory Factor (SRF), Tissue Respiratory Factor (TRF), andProcytoxoid (PCO). The product, LYCD, is an alcoholic extract of viableSaccharomyces cerevisiae. The material is produced and marketed byLanger Laboratories, a subsidiary of Sperti Drug Co. of Erlanger, Ky. asa standard article of commerce. Other producers of LYCD are MDHLaboratories, Inc., Cincinnati, Ohio 45210, and Universal FoodsCorporation, Fermentation Division, Milwaukee, Wis. 53202. LYCD isavailable for experimental use as a bulk drug assaying 5 units to 40units/mg of respiratory activity. In topical medicinal preparations itis characterized and quantified in terms of Skin Respiratory Factor(SRF) units. A unit of activity is calculated as the amount of SRF whichis required to increase the oxygen uptake of 1 mg of dry weight ratabdominal skin by 1 percent at the end of a 1 hour testing period in aWarburg apparatus.

LYCD is also available as LYCODERM® ointment containing 2,000 units SkinRespiratory Factor (SRF) per ounce, from Arel Pharmaceuticals, Inc.,Cincinnati, Ohio. In the prior art the well known hemorrhoidal ointment,PREPARATION H®, contains 2000 units of SRF (ca 1%) per ounce ofointment.

J. Z Kaplan (Arch. Surge. 119(9) p. 1005-8 (1984) has reported that, ina double blind human skin graft study donor sites treated with LYCDointment, statistically significant earlier angiogenesis andepitheliazation occurred as compared with donor sites in the samepatients treated with ointment bases (without LYCD). This studyconfirmed earlier laboratory reports such as that of Wm. Goodson et. al.Journal of Surgical Research 21: 125-129 (1976) showing that LYCD iscapable of stimulating wound oxygen comsumption, epitheliazation, andcollagen synthesis.

As reported in the Cincinnati Inquirer of Dec. 12, 1986, Ashlley HunterCosmetic Co. offers a facial cream containing LYCD to minimize wrinkles.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide pharmaceuticalcompositions suitable for the treatment of various ailments and physicalconditions of the skin such as acne, bed sores, burns, infections,trauma, ulcers, wounds, and wrinkles.

It is a further object to provide compositions of the type describedwhich are more effective than compositions presently known in the art.

The foregoing and other objects, advantages and characterizing featureswill become apparent from the following description of certainillustrative embodiments of the invention.

According to the invention, pharmaceutical compositions are provided byutilizing LYCD in combination with certain known pharmaceutical agentsor remedies. The LYCD acts synergistically with these other agents toprovide a composition having greater effectiveness than that of theindividual agents, and a greater effectiveness than could be predictedby combining (in an additive fashion) the known or theoreticaleffectiveness of the individual ingredients.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The compositions of the invention may be produced by either of twogeneral methods. In the first method, for example, an ointmentcomposition may be formulated by mixing LYCD with conventionalointment-forming ingredients. One such ointment composition isLYCODERM®. a registered trademark material marketed by ArelPharmaceuticals, Cincinnati, Ohio, having the following compositions:

    ______________________________________                                                              Per 100 Parts                                           ______________________________________                                        Beeswax                 4.0                                                   Lanolin                 4.0                                                   Petrolatum              87.9                                                  Shark liver oil         3.0                                                   Phenyl mercuric nitrate  0.01                                                 T.R.F. (LYCD) (2,000 units/ounce)                                                                     1.0    approx.                                        Thyme oil               0.1                                                   ______________________________________                                    

PROCEDURE

In preparing the above compositions, the beeswax, petrolatum, sharkliver oil and phenyl mercuric nitrate are treated together to atemperature of 140 deg. F. in a steam-jacketed s.s. kettle. Thematerials are mixed until the mixture is uniform. Then the steam isturned off and cooling water is introduced while mixing is continued.When the mixture has reached a temperature of 110 deg. F., the T.R.F.and thyme oil are added. When the composition becomes uniform, mixing isstopped. Filling may be carried out at temperatures of between 90 and110 deg. F.

In utilizing the first method of producing the compositions of theinvention, the LYCODERM® ointment as produced above but utilizing 200 to1800 TRF units per ounce of formulation is mixed with the knownpharmaceutical agent by a conventional method.

The second method of carrying out the present invention comprises mixingbulk LYCD into the conventional pharmaceutical composition.

In general, it has been found that effective compositions are formulatedusing LYCD concentrations in the range of 0.1% to 3%, e.g., 0.1% to 2%by weight of the composition, for example 10% to 50% of that employed inthe basic LYCODERM® ointment formulation. This translates into 200 to1000 TRF units per ounce of combined product. Stated in another way, thenew compositions have a LYCD concentration of approximately 0.1% to 0.5%compared with approximately 1.0% LYCD/TRF in the basic LYCODERM®formulation. However, for certain compositions LYCD/TRF in the amount of0.8% of the total composition produces optimum results.

Correspondingly, the other active components of the new compositions arefound to be synergistically efficacious at concentrations in the rangeof 5% to 50% of that found to be efficacious in marketed pharmaceuticalproducts.

A. Antiinfective Compositions EXAMPLE 1

The above-described LYCODERM® ointment was formulated using 1000 unitsof TRF per ounce. To this formulation was added sufficient 2%erythromycin to yield an ointment containing 0.5% LYCD/TRF and 1%erythromycin. In a controlled clinical trial this composition wasequally effective in the topical control of acne vulgaris as aconventional 2% ointment preparation of erythromycin. (An example ofsuch a medicinal preparation, NDA 50-584, Akneymycin Topical Ointment,2%, is a topical erythromycin accepted by the FDA for topical control ofacne vulgaris.)

EXAMPLE 2

Alternatively, a marketed anti-acne 2% Erythromycin product wasreformulated as follows:

    ______________________________________                                        Erythromycin Base    1%       w/v                                             LYCD/TRF             0.5%     w/v                                             Alcohol              55%      v/v                                             Oleyl Alcohol        5%       w/v                                             Perfume              q.s.                                                     Propylene Glycol     to 100%                                                  ______________________________________                                    

Following the same treatment regimen, the 1% Erythromycin solutioncontaining approximately 0.5% LYCD of Example 2 (assaying 1,000 units ofTRF per ounce of formulation) was found to be more effective than asimilar 2% Erythromycin solution without LYCD in the treatment of Acnegrades 2 and 3 (moderate to severe).

EXAMPLE 3

In an analogous fashion, Lincomycin Hydrochloride or ClindamycinPhosphate at a concentration of 0.5% is combined with 0.5% LYCD/TRF inthe LYCODERM® formulation to provide an ointment as effective intreating common acne as the conventional 1% Clindamycin Phosphatetopical medication, and more effective than either agent individually orpredictable in their combination.

EXAMPLE 4

More specifically, ten patients suffering with severe acne completelyrefractory to months of prior treatment with a variety of conventionalacne medications were treated with an admixtured combination of CleocinT (clindamycin phosphate solution) and LYCODERM® Ointment. The finalformulation contained approximately 0.34% clindamycin and 0.56% LYCD.Each subject applied this formulation twice daily for 30 days with thefollowing results:

Patient 1: female, age 16: Refractory to Acromycin, Erythrocin, diet,local treatment. The patient was subsequently treated with the low dosecombination product of Example 4, and as a result experienced 80%improvement.

Patient 2: male, age 25: Refractory to Achromycin, curattage, Acutane.The patient was then treated with the low dose combination product ofExample 4, and as a result experienced 90% improvement.

Patient 3: male, age 30: Refractory to proprietary medicines,Erythromycin, Achromycin, Fostex (10% Benzoyl Peroxide). The patient wasthen treated with the low dose combination product of Example 4, andexperienced 50% improvement.

Patient 4: female, age 21: Refractory to astringents, Erythromycin, anddiet. The patient was then treated with the low dose combination productof Example 4, and experienced 85% improvement.

Patient 5: Female, age 18: Refractory to Achromycin, diet, andastringents. The patient was subsequently treated with the low doseformulation of Example 4, and experienced almost 100% improvement.

Patient 6: female, age 24: Refractory to Achromycin, curettage, anddiet. The patient was subsequently treated with the low dose formulationof Example 4, and experienced 85% improvement.

Patient 7: female, age 24: Refractory to Achromycin, diet, local Rx, andproprietary drugs. The patient was subsequently treated with the lowdose formulation product of Example 4, and experienced 85% improvement.

Patient 8: female, age 29: Refractory to Vitamin A ointment, diet, andAchromycin. The patient was subsequently treated with the low doseformulation of Example 4, and experienced 80% improvement.

Patient 9: male, age 30: Refractory to Achromycin, local Rx, andAcutane: The patient was subsequently treated with the low doseformulation of Example 4, and experienced 80% improvement.

Patient 10: female, age 20: Refractory to Achromycin, and coal tarproducts. The patient was subsequently treated with the low doseformulation of Example 4, and experienced 85% improvement.

EXAMPLE 5

In an analogous fashion 5% or 10% Benzoyl Peroxide anti-acneformulations were admixed with LYCODERM® ointment to provide low doseBenzoyl Peroxide/LYCD combination products more effective than thehigher concentration of Benzoyl Peroxide in the treatment of acnevulgaris. Additionally, desquamation, symptoms of burning, and otherside effects were less frequent.

Thus 1.5 oz, FOSTEX® 5% Benzoyl Peroxide Gel was admixed with 2 oz. LYCDointment to provide a formulation containing approximately 2% BenzoylPeroxide and 0.5% LYCD. Further 1 oz. of CLEARASIL®, 10% benzoylperoxide anti-acne cream, was admixed with 4 oz. of LYCODERM® ointmentto provide a formulation containing approximately 2% benzoyl peroxideand 0.8% LYCD

EXAMPLE 6

Alternatively, the compositions of the present invention ae formulatedby incorporating LYCD/TRF itself into known formulations ofantibacterial agents. For example, two commonly used antibiotic firstaid ointments are indicated to help prevent infection and aid in thehealing of minor cuts, burns, and abrasions. One such antibioticpreparation contains 0.5% neomycin sulfate. The second contains 500units of bacitracin, 5000 units of polymyxin B sulfate, and 0.5%neomycin sulfate per gram of composition. To each of these formulationswas added 1000 units of LYCD (approximately 0.5%) per ounce of product.The resulting LYCD antibiotic compositions were synergistically moreeffective for topical first aid use than the components when usedseparately.

EXAMPLE 7

In an analogous example, a LYCODERM®/antibiotic combination ointmentproduct was formulated as follows:

    ______________________________________                                        Polysorbate 80   2        pounds  1.00% w/w                                   Polymixin B (7,700 iu/mg)                                                                      117.02   grams   0.129%                                                                              w/w                                   Bacitracin Zinc (690 u/mg)                                                                     656.81   grams   0.724%                                                                              w/w                                   Phenyl Mercuric Nitrate                                                                        9        grams   0.01% w/w                                   LYCD/TRF (12 u/mg)                                                                             266.7    grams   0.50% w/w                                   Deionized water  4# 7     oz      2.50% w/w                                   Beeswax (white)  8# 1     oz      4.00% w/w                                   Lanolin          8# 1     oz      4.00% w/w                                   Petrolatum       167# 13  oz      83.93%                                                                              w/w                                   Shark liver oil  6# 1     oz.     3.03% w/w                                   Thyme oil        90       grams   0.10% w/w                                   ______________________________________                                    

Procedure

In preparing the above composition, the first four ingredients weremixed and suspended well. The LYCD/TRF is dissolved in the water andmixed well with the first ingredients. The resulting solution was heatedto 140° F.

Separately, the third group of ingredients was mixed in a cleancontainer and heated to 160° F. with good mixing the first solution wasadded to the contents of the container; the thyme oil was then added andthe composition permitted to cool to 60°-80° for filling intocontainers.

The product thus produced is ideal for treating minor cuts, burns, andscratches. It appears to work rapidly and especially well on infants andchildren, where the ointment formulation functions somewhat like anocclusive dressing

EXAMPLE 8

A similar LYCODERM®/antibiotic ointment formulation was also preparedusing LYCD/TRF at a concentration of approximately 1.0% (2000 unitsTRF/oz of product).

Used twice a day for two to four weeks as an emollient in a group of 10elderly patients suffering from bed sores, this product resulted in 50to 100% healing.

Topical antiinfective compositions for wounds including burns may beprovided utilizing LYCD/TRF in combination with silver sulfadiazine anda suitable ointment-forming base, or LYCD/TRF in combination withpovidone-iodine and a suitable ointment-forming base.

EXAMPLE 9

Topical antifungal compositions are used in the treatment of cutaneousor mucocutaneous mycotic infections caused by Candida species,pathogenic dermatophytes, other yeasts, and various superficial fungalinfections of the skin. Tolnaftate UPS at the level of 0.5%, whenformulated with LYCODERM® containing LYCD/TRF at a concentration of 1000units per ounce (ca 0.5%) provides a synergistic composition moreeffective than the standard topical antifungal preparation containing1.0% of Tolnaftate. In an analogous manner, Nystatin USP at aconcentration of 50,000 units per gram when formulated with LYCD/TRF atthe 0.5% concentration, and chlortrimazole 0.25% provided compositionsequal in antifungal effectiveness with the topical antifungals usedalone at 3 and 4 times the concentration employed in the compositions ofthe invention.

EXAMPLE 10

Thus 30 cc of clotrimazole solution, USP 1%, was admixed with 3 oz. ofLYCODERM® ointment, and the resulting combined formulation used to treata severe tinea pedis infection in a 70 year old male. With twice a dayapplication into the affected and surrounding skin areas, the infectioncleared up within a week.

EXAMPLE 11

Topical antiviral medicinal agents are licensed by the FDA particularlyfor the treatment of herpes simplex and herpes genitalis. The agentidoxuridine is marketed as a 0.5% ointment. When formulated as a 0.1%concentration of idoxuridine and 0.5% concentration of LYCD/TRF(containing 1000 units per ounce), the topical composition showedsynergistic antiherpes simplex viral activity. Similarly, a topicalcomposition containing 0.5% acyclovir and 0.5% LYCD (containing 1000units of TRF per ounce of LYCODERM® ointment formulation) gave betterresults in the treatment of herpes genitalia than would be anticipatedfrom the known antiherpes activities of acyclovir in the absence ofLYCD. The antiviral efficacy of topical formulations of alpha, beta, orgamma interferons (used at doses of 3 million to 10 million IU) per 30ml. solution are also enhanced synergistically by the addition of 0.1%to 0.5% of LYCD representing 200 to 1000 units of TRF per ounce oftopical composition.

In laboratory cell culture studies, the effect of LYCD, lymphokines andlymphokine modulating chemicals on vaccinia virus infected monkey kidneyBSC-40 cells, or human epidermoid A431 cells was investigated. Vacciniavirus is a DNA virus, as is herpes.

EXAMPLE 12

Pre-treated experiments: Each cell line was pretreated with a candidateantiviral compound for 24 hours, washed, and then infected with lowmultiplicities of vaccinia. After 24 hours of infection, virus wastitered on BSC-40 monolayers. The data is expressed in placque-formingunits (PFU); and the results of duplicate experiments averaged.

Post-infection experiments: Vaccinia infected cells were exposed to thetest material for 24 hours.

The 24 hour preincubation of BSC-40 cells with 100 to 200 milligrams perml. of LYCD, followed by vaccinia virus infection resulted in a 30% to40% reduction in PFU. Higher concentrations of LYCD did notquantitatively change the viral inhibition.

EXAMPLE 13

The immunomodulating drug Tilorone, and two of its analogs, RMI-11567,and RMI-11645 were similarly tested for their ability to induce anantiviral state in BSC-40 cells by pretreatment of the cells for 24hours. (See Progress in Medicinal Chemistry, vol. 18, pp. 136-190, 1981for a description of these compounds) In these experiments 2-3micrograms per ml. of the tilorones resulted in an inhibition of viralgrowth which peaked at 40%, with RMI 11567 being the most active.

EXAMPLE 14

In analogous experiments, pretreatment with the lymphokines gammainterferon, and Interleukin-I (IL-1) at even lower doses (250 units perml. and 10 units per ml., respectively) resulted in a 60% to 90%stimulation of viral growth. However, combination of each of thesematerials with 100 micrograms per ml. of LYCD synergistically reduced orreversed this stimulation.

EXAMPLE 15

Surprisingly, in Post-infection cell culture experiments, 1 microgramper ml. of RMI-11567 and 100 micrograms per ml. of LYCD each separatelycaused a 30% stimulation of viral growth; however, the combination ofRMI-11567 and LYCD resulted, synergistically, in a 15% inhibition ofvaccinia growth as measured by placque forming units (PFU). The percentstimulation/inhibition was calculated by comparing the PFU to concurrentcontrol experiments which did not contain any drug.

EXAMPLE 16

In analogous Post-Infection studies with A431 cells, somewhat similarresults were obtained. Thus 8 (standard) units per ml. of alpha or betaInterleukin-I resulted in a slight (3%) inhibition of vaccinia growth asmeasured by PFU; and 100 micrograms per ml. of LYCD resulted in an 18%inhibition of PFU. The combination of 8 units per ml. of IL-1 and 100micrograms per ml. of LYCD resulted in a synergistic 32-35% inhibitionof viral growth as measured by placque-forming units (PFU).

The experiments described in the examples above demonstrate that in cellculture LYCD has significant antiviral activity which cansynergistically enhance the antiviral effects of some lymphokines andlymphokine modulating chemicals.

As more fully described on page 14, line 18 below, a standardized LYCDpreparation assaying 12 units of Tissue Respiratory Factor (TRF) per mg.was used in the above described cell culture studies.

EXAMPLE 17

The addition of 0.5% fluorouracil to the above-described LYCODERM®ointment formulated with 1000 units of TRF (about 0.5%) per ounce ofproduct provides a composition for the topical treatment of multipleactinic (solar) keratoses which is synergistically more effective than aconventional topical preparation formulated with 1.0% fluorouracil.

Antiinflammatory Compositions EXAMPLE 18

Triethanolamine salicylate (10%) is formulated in lotions and creams toprovide a topical external analgesic agent for temporary relief fromminor pains of arthritis, rheumatism, and muscular aches. Whenformulated using 5% of triethanolamine salicylate and 200 to 1800 unitsTRF per ounce of product (equivalent to approximately 0.1% to 0.8% ofLYCD), the new composition was synergistically more effective than theoriginal analgesic product containing 10% of triethanolamine salicylate.In an analogous manner, when LYCODERM® is formulated with non-steroidalantiinflammatory agents such as ibuprofen or its isomers (at a level of1.0% to 5.0%), the resulting topical compositions have a level oftopical anti-inflammatory efficacy not demonstrated by the samepreparation of the non-steroidal antiinflammatory agent (NAIA)formulated without LYCD/TRF.

The adreno-corticoid steroids demonstrate pleitropic activity in cellculture systems and as topical antiinflammatory agents.

Metabolically, LYCD/TRF biological activity at the cellular level inanimal and human skin results in an increase in oxygen respiration andcell growth. However, in specific human cell lines including humanfibroblasts, the effects are variable.

EXAMPLE 19

A number of standard human cell lines were evaluated and methodology wasdeveloped leading to the use of A431 cells, Am Type Culture CollectionCLL 1555, as a suitable human cell line to study the effect of LYCD onoxygen respiration and cell growth. In order to facilitate study of themetabolic interaction of LYCD with lymphokines, cytokines, other growthfactors, and topically useful therapeutic agents, it was necessary toachieve reproducible base line results in a defined serum-free cellculture medium. Cell respiration was quantified using a Clark oxygenelectrode oxygraph apparatus. Experiments were done in duplicate, andcell number measurements were always done in quadruplicate, for anysingle experiment, the amount of (oxygen) respiratory stimulation orinhibition of a measured number of A431 cells can be correlated with theconcentration of added LYCD. Respiration is measured within 6-10 minutesof adding the LYCD and/or other substrates.

A standardized LYCD preparation assaying 12 units of TRF/mg. was used inthese studies. In a typical titration of A431 cell respiration it wasfound that 0.75 to 1.25 mg/ml of LYCD resulted in about a 60% increasein respiration. An LYCD concentration of 0.15 mg/ml gave a 10 to 15%increase in respiration; and 1.50 mg/ml of LYCD resulted in a 20%increase in respiration. Higher concentrations of LYCD were almostcompletely inhibitory of respiration.

EXAMPLE 20

In companion experiments it was determined that 25 to 35 picomolarconcentrations of hydrocortisone inhibited A431 respiration, but, whenadded together with LYCD synergistically doubled the respiratorystimulation of 0.2 mg/ml LYCD from 20% to 40%.

A431 cell growth experiments were compared at seven days using astandard commercial serum-free medium (Gibco DME, Dulbecco's MinimumEssential media) and ITS (5 micrograms/ml each of insulin, transferinand selenium).

It was found that a 0.70 mg/ml of LYCD caused significant andreproducible growth of A431 cells. This concentration of LYCD representsabout 12% of the concentration of LYCD found in presently marketedproducts containing LYCD.

LYCD concentrations of 0.02 mg/ml provided a 30% enhancement in A431cell growth.

Hydrocortisone has been reported in the literature to be an inhibitor ofA431 cell growth.

EXAMPLE 21

A seven day study was made to determine the effect of hydrocortisone oncell growth. It was found that hydrocortisone at the very lowconcentration of 1×10⁻⁸ mg./ml. inhibits A431 cell growth by 65%.However, it was further surprisingly found that the combination of thehydrocortisone plus 0.75 mg/ml of LYCD enhances cell growth by 200%.

EXAMLE 22

A LYCODERM®/hydrocortisone ointment combination product for topicalantiinflammatory therapy was formulated as follows:

    ______________________________________                                        Ingredient       Amount      % w/w                                            ______________________________________                                        Polysorbate 80   2       pounds  1.00                                         Hydrocortisone Acetate                                                                         1       pound   0.50                                         Phenyl Mercuric Nitrate                                                                        9.0     grams   0.01                                         LYCD/TRF (12 u/mg)                                                                             533.34  grams   1.0                                          Deionized water  2.25    pounds  2.0                                          Beeswax (white)  8 lb. 1 oz. 4.04                                             Lanolin          8 lb. 1 oz. 4.04                                             Petrolatum       168.5   pounds  84.28                                        Shark Liver Oil  6 lb. 1 oz. 3.03                                             Thyme Oil        90      grams   0.10                                         ______________________________________                                    

Procedure

The first 3 ingredients were combined and mixed well. The LYCD wasdissolved in water, combined with the first group and mixed well. Thethird group of ingredients was added to a clean container, heated to160° F. with good mixing. With stirring, the water mixture was heated to140° F. and added to the petrolatum preparation in a container. Whilestirring continued the mixture was cooled to 100° F. then the thyme oilwas added and the mixture further cooled to 60°-80° F. for filling. Theformulation thus prepared was found to provide a superior topicalantiinflammatory product.

Herpes zoster (shingles) is an acute inflammatory disease of thecerebral ganglia and ganglia of the posterior nerve roots, caused by thevirus of chicken pox. It is characterized by groups of small vesicles oninflammatory bases occurring in cutaneous areas supplied by certainnerve trunks, and associated with neuralgic pain.

Severe clinical herpes zoster is generally not helped by treatment withpresently available antiviral/anti-inflammatory medications.

EXAMPLE 23

A number of herpes zoster patients were treated by Sidney Peerless, M.D.of E.N.T. Associates, 3131 Harvey Avenue, Cincinnati OH 45229. Thetreatment was carried out after failure of conventional medication, andcomprised treatment with a composition according to the presentinvention comprising the LYCODERM®/Hydrocortisone Acetate formulationshown above in Example 22.

Patient 1: This patient had shingles of 4 weeks duration, herpes of theright face and forehead. Symptoms: severe pain, breaking out pustules,and redness. Previous treatment: Zovirex capsules, Zovirex ointment, andantibiotics did not help. The patient was placed onLYCODERM®/Hydrocortisone Acetate ointment of Example 22 applied 2-4times per day to the affected areas. In 3 days the patient showed markedimprovement, especially in the pustules and also in the pain threshold.Within 10 days the lesions were improved and the patient felt muchbetter symptomatically.

Patient 2: The patient had severe shingles in the cervical area goinginto the lower portion of the jaw and into the neck characterized bypustules, severe pain and erythema. Under previous treatment by adermatologist he had received steroids systemically and Zoviraxointment. After having the disease for three weeks he came to see Dr.Peerless in desperation, because of the severe pain he experienced. Thepatient also had herpes lesions in his throat. He was placed on theLYCD/Steriod combination ointment of Example 21. After 10 days oftreatment the entire facial and neck lesions were gone. There was amarked diminution of pain and need for Demerol, and his generalcondition improved greatly.

Patient 3: The patient had severe shingles involving the right posteriorleg and up to the dorsum of the foot. Under the care of anotherphysician the patient had received steroids, antibiotics systemically,and an antibiotic ointment, Polysporin, applied to the lesions withoutimprovement. The patient came to see Dr. Peerless also in desperation.She was placed on the LYCD/steroid combination ointment of Example 21.After three weeks the lesions were almost completely cleared. The painfactor was gone. The patient was able to wear her shoe and showedoverall marked improvement.

Patient 4: This patient had shingles of the lower lumbar area along thenerve root with large pustules, erythema and almost uncontrollable pain.He had been on pain medicine and Zovirax. He had also been givensystemic antibiotics and steroids with very little improvement. Thepatient was placed on the LYCODERM®/Hydrocortisone Acetate ointment ofExample 22. In 48 hours his condition improved markedly, especially inreduction of pain. After another 4-5 days on the medication the herpeticlesions were almost completely under control, and medication wascontinued for another week. Three weeks after stopping the medication,the patient had a recurrence of the herpes. Readministration of theLYCD/steroid ointment of Example 22 for two weeks again brought theherpes under control, and the patient has remained well.

EXAMPLE 26

A formulation was analogously prepared in which the hydrocortisoneacetate concentration was reduced to 0.1%. This formulation was found toenhance the anti-erythema, wound-healing properties of the combinationproduct.

EXAMPLE 27

Alternatively, LYCD/TRF at levels of 200 to 1800 units per ounce(approximately 0.1% to 0.8%) are added to conventional formulations(creams, lotions, ointments, gels, etc.) of compatible topicaladrenocorticoid formulations which are used in concentrations of 0.01%to 1.0% to produce synergistic therapeutic compositions providing moreeffective medication for the same indications presently approved by theFDA.

A representative listing of Topical Adrenocorticoids which may be usedin formulating compositions according to the present invention maybefound in the U.S. Pharmacopeial Convention 1986 publication "THEPHYSICIANS' AND PHARMACISTS' GUIDE TO YOUR MEDICINES", published byBallantine Books, N.Y.N.Y.

EXAMPLE 28

More particularly, the addition of 0.25% hydrocortisone acetate to theLUCODERM® formulation containing 1000 units of LYCD/TRF per ounce ofointment (approximately 0.50%) results in a topical antiinflammatorymedicinal composition with greater activity and efficacy than ispresently available in any topical steroid product licensed by the U.S.FDA for OTC (over the counter) use.

Wound Healing Compositions

Live yeast cell derivative (LYCD) per se increases collagen formation.It is accepted in the art that most agents promoting experimental woundhealing appear to act primarily to promote collagen synthesis.Controlled clinical studies of LYCD have demonstrated both clinicallyand statistically earlier angiogenisis, initiation and completion ofepithelialazation, and acceleration of wound healing.

The use of a composition such as LYCODERM® formulated with 2000 units ofLYCD/TRF per ounce of ointment (about 1.0%), and also containing 3% ofshark liver oil has also been shown clinically to promote wound healing,including a range of first, second and third degree burn wounds.

Separately, a number of lymphokine/cytokine proteins have been foundwhich enhance wound healing by directly activating macrophages orindirectly stimulating the skin immune system. More than several dozenof these naturally occurring growth factors have been reported in theliterature, but are difficult to isolate and characterize, and mayactually overlap in identity. Therapeutic doses, although measured infractions of milligrams, are very costly.

EXAMPLE 29

Epidermal Growth Factor (EGF) is one such growth factor which has beenused topically at a concentration of 0.0001% to accelerate normal woundhealing by 15-20 percent. According to the method of the presentinvention, compositions containing 500 units of LYCD as TRF(approximately 0.25% and 0.0001% EGF are synergistically more effectivein treating chronic epidermal ulcers. Similarly using LYCD/TRF at 0.1%to 0.5% concentrations (equivalent to 200-1000 LYCD/TRF units per ounceof product) in compositions with Fibroblast Growth Factor (FGF),Platelet-Derived Growth Factor (PDGF), Transforming Growth Factor-alpha(TGF-alpha), Transforming Growth Factor-beta (TGF-beta), or Insulin-likeGrowth Factor-1 (IGF-f) has provided synergistic wound healingcompositions. Both partial and full incisional wounds show synergistichealing patterns. Compositions consisting of several of these growthfactors formulated with LYCD/TRF as in LYCODERM® also result insynergistically acting wound healing products.

EXAMPLE 30

In another embodiment of this invention lymphokine/cytokine modulatingchemicals, such as Tilorone and its congeners, are formulated intotopical wound healing compositions in combination with LYCD/TRF. Thusthe LYCODERM® formulation previously described is prepared using 1000units of LYCD/TRF per ounce (ca 0.5% and 0.1% of Tilorone to produce asynergistically effective ointment for the treatment of severe burnwounds and non-healing epidermal ulcers. Depending on the formulation,Tilorone synergy can be demonstrated at concentrations ranging from0.01% to 0.5% in epithelial tissue repair experiments.

Anti-Skin Wrinkling Compositions EXAMPLE 31

Skin wrinkling is accelerated by deficiencies in collagensynthesis/metabolism. Vitamin A acid (all-trans retinoic acid) is usedas a topical preparation to slow or reverse the process of wrinkling.However, its use it limited by concentration related toxicity. Accordingto the present invention LYCD/TRF compositions synergistically augmentthe anti-wrinkling actions of topical retinoic acid with no increase intoxicity. Thus the LYCODERM® formulation previously described isprepared using 1000 units of LYCD/TRF per ounce (ca 0.5%) and 0.25% ofvitamin A acid to provide a topical ointment composition synergisticallymore effective than retinoic acid in ameliorating the skin wrinklingprocess, including photo-aged skin.

EXAMPLE 32

Alternatively, presently used cream (0.1%), gel (0.025%), or liquid(0.05%) Vitamin A acid formulations are augmented with 0.5% of LYCD/TRF(about 1000 units per ounce to provide synergistically more effectiveanti-wrinkling compositions. Additionally, these novel compositions arebeneficial in treating ichthyosis, actinic keratosis and otherhyperkeratotic conditions.

LYCD/TRF may also be combined with other retinoic acid congeners, knowncollectively as retinoids, which are also useful topical anti-wrinklingagents to produce new compositions as covered by the present invention.A number of these epidermally acting retinoids are described, forinstance, in the special issue supplement to The Journal of the AmericanAcademy of Dermatology (Volume 15, No. 4, Part 4, October 1986 entitled"TOPICAL RETINOIDS: AN UPDATE").

The compositions of the present invention comprising LYCD/TRF incombination with other topically active medicinal ingredients have manyadvantages over conventional products. The presence of the LYCD/TRF inthe compositions provides a synergistic effect which makes theconventional materials more effective and permits less of theconventional ingredients to be used whle still achieving the sameresults.

The compositions of the present invention contain, in addition toLYCD/TRF and the other pharmaceutically active ingredient, a carriersuitable for rendering the composition as a formulation to be used fortopical applications. In one method for forming the compositions of thepresent invention the carrier is provided by the LYCODERM®. In anothermethod the carrier is provided by the commercial form of the otheractive ingredient. Alternatively, a suitable carrier known in the artmay be added to both the LYCD/TRF and the other active ingredient. Inall examples above the indicated percent content of the statedingredients is based on the weight of the total ingredients, theLYCD/TRF, the other pharmaceutically active ingredient, and the carrier.

Although the invention has been described in connection with specificembodiments thereof, it is evident that many alternatives,modifications, and variations will be apparent to those skilled in theart in the light of the foregoing description. Accordingly, it isintended to embrace all such alternatives, modifications and variationswithin the spirit and scope of the invention as defined by the appendedclaims.

Invention is claimed as follows:
 1. A topical composition adapted forapplication to the skin comprising, in admixture with a pharmaceuticallyacceptable topical carrier, an antiinflammatory agent and, from about0.1% to about 3.0% by weight of said composition of Live Yeast CellDerivative (LYCD) in amounts effective to ameliorate the neuralgic gainassociated with a herpes infection when applied to an area of the skinproximate the pain.
 2. A composition according to claim 1, wherein saidLYCD/TRF is present in an amount of from about 0.1% to about 1.0% byweight of said composition.
 3. A composition according to claim 1,wherein said antiinflammatory agent is a steroid.
 4. A compositionaccording to claim 1, wherein, said LYCD is present in an amount of fromabout 0.1% to about 0.8% by weight of said composition.
 5. A compositionaccording to claim 4, wherein said antiinflammatory agent istriethanolamine salicylate.
 6. A composition according to claim 4,wherein said antiinflammatory agent is cortisone.
 7. A compositionaccording to claim 4, wherein said antiinflammatory agent ishydrocortisone or esters derived thereof.
 8. A method for amelioratingthe topical symptoms associated with a herpes infection in a humanbeing, which comprises topically applying to an area of the skin of saidhuman being where the symptoms are manifested an effective amount of acomposition of claim
 1. 9. A method according to claim 8, wherein andsaid LYCD is present in an amount of from about 0.1% to about 0.8% byweight percent of said composition.
 10. A method aaccording to claim 9,wherein said antiinflammatory agent is triethanolamine salicylate.
 11. Amethod according to claim 10, wherein said antiinflammatory agent isibuprofen or an isomer thereof.
 12. A method according to claim 10,whrein said antiinflamatory agent is cortisone.
 13. A method accordingto claim 10, wherein said antiinflammatory agent is hydrocortisone or anester thereof.
 14. A method according to claim 13, wherein said herpesinfection is shingles.
 15. A method according to claim 8, wherein theinfecting virus is herpes zoster, wherein the symptoms of the infectioninclude neuralgic pain, and wherein the antiinflammatory agent is asteroid.
 16. A method according to claim 15, wherein the symptomsfurther include a skin lesion.
 17. A method according to claim 15,wherein the antiinflammatory agent is hydrocortisone or an esterthereof.
 18. A method of claim 17, wherein the antiinflammatory agent ishydrocortisone acetate.